Insulin discovery from Case Western Reserve University and international team may mean better treatment, no needles

A woman fills a syringe as she prepares to give herself an injection of Insulin.Associated Press

CLEVELAND, Ohio-- The discovery of insulin in 1921 was lifesaving for millions of diabetics, offering a way to manage what had been a deadly disease with daily medication.

But since then, little has been learned about exactly how the hormone does its work in the body's cells, allowing them to transform sugar into energy. That knowledge gap has been a barrier to developing new treatments for the disease -- most patients today still need several injections of insulin a day to remain healthy.

Now, researchers at Case Western Reserve University are part of an international team that has discovered, in 3-D, what insulin looks like when it makes contact with cells.

"These findings carry profound implications for diabetes patients," saidDr. Michael Weiss, Case Western Reserve biochemistry professor and department chair and one of the study's authors. "Short term, this will mean making better insulin. Long term, it could mean getting rid of needles and pumps altogether."

The team's study was published online last week in the journal Nature.

CWRU researcher Michael Weiss has been studying insulin since 1985. He hopes to soon have forms of insulin that patients can take once a day, or even once a week, to manage their diabetes.Case Western Reserve University

The 17-member research team also included CWRU associate professor of biochemistry Jonathan Whittaker and research assistant (and spouse) Linda Whittaker, and members from the University of York in the United Kingdom; the Walter and Eliza Hall Institute of Medical Research in Australia; La TrobeUniversity and the University of Melbourne in Melbourne, Australia; Academy of Sciences of the Czech Republic in Prague; and the University of Chicago.

"They've done something that's not been done so far, and understanding how all these mechanisms work is very important," said Dr. Mario Skugor, an endocrinologist at the Cleveland Clinic.

What the research team figured out, and described in minute detail in the Nature paper, is the three-dimensional structure of insulin and a protein to which it binds on the surface of every cell in the body, called an insulin receptor.

If you remember basic biology, this binding process is the first step in getting anything to happen inside our bodies, and it takes place at the microscopic level of individual cells.

Insulin, a hormone that regulates the metabolism of sugars and fats, is produced naturally in the body to remove excess sugar from the blood. It does this by binding to the insulin receptors on cells, which then triggers a cascade of reactions telling those cells to transport sugar into the cell.

In diabetics, who either do not produce their own insulin (Type 1 diabetes) or who have become desensitized to the effect of insulin in their bodies (Type 2 diabetes), injection of insulin gets this job done. Without it, blood sugar can remain dangerously high even as cells starve for energy, leading to heart disease, stroke, blindness, kidney failure and death.

Weiss and the international team figured out the insulin-receptor structure by a complicated combination of X-ray imaging and genetic engineering.

"We used site-directed photo cross-linking made possible by the extended genetic code," said Weiss.

Yeah, I didn't really understand much of that, either. Suffice it to say it wasn't easy. The research team has been working on the many parts that went into the discovery since 1991.

"That is a very tedious and complex study to do," Skugor said. "They showed exactly how it works, and that will allow other people with this knowledge to look at any kind of potential new drug that would work at that receptor."

"This discovery should provide fresh insights into the design of new forms of insulin that are more potent than those that are currently used in diabetes treatment," Stevan Hubbard, professor of biochemistry and molecular pharmacology at NYU School of Medicine said in an email. Hubbard wrote an editorial accompanying the Nature paper.

And the benefit may not be limited to diabetes patients, Skugor said. Insulin isn't the only hormone that binds to the insulin receptor on cells, and the insulin pathway is also involved in the growth and division of cells, making it a potential target of cancer therapies.

Skugor said it's impossible to predict where the research might lead, but "people are very inventive and could come up with a lot of uses for this."

"This is a great step forward," he said. "It's really quite impressive."

Weiss' team at CWRU is still hard at work. While the Nature paper described much of the insulin receptor, it's a complex protein and there are still two missing pieces that will complete the picture. The researchershave submitted another paper for publication describing one of them, and believe they found the last missing piece over the holidays.

Their "medium term" goal is to make better insulin, Weiss said. The lab has been working for several years on an ultra-high-heat stable insulin that doesn't require refrigeration, and hopes to produce insulin that can be used once a day or even once a week.

In the long term, he and his colleagues would like to get a fuller picture of the hormone and its receptor in both the "on" (or bound) and "off" (or unbound) states in the cell.

"Nature has evolved this fancy car, with six cylinders and power brakes and windows, and we've only glimpsed part of the engine now," he said.

It may be 10 years or longer before their discovery leads to new treatments for diabetes. But it's a crucial key step in the right direction for millions of people who have the disease.

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